
==== Front
Drugs Real World Outcomes
Drugs Real World Outcomes
Drugs - Real World Outcomes
2199-1154
2198-9788
Springer International Publishing Cham

38914856
433
10.1007/s40801-024-00433-2
Original Research Article
Falls and Fractures among Nursing Home Residents Treated with Pimavanserin versus Other Atypical Antipsychotics: Analysis of Medicare Beneficiaries with Parkinson’s Disease Psychosis
http://orcid.org/0000-0002-4878-0822
Rajagopalan Krithika kr.rajagopalan@anlitiks.com

1
http://orcid.org/0000-0002-4227-1234
Rashid Nazia 2
Gopal Daksha 1
Doshi Dilesh 2
1 Anlitiks Inc, 4320 Isabella Circle, Windermere, FL 34786 USA
2 https://ror.org/030bhbq32 grid.417646.6 0000 0004 0407 8796 Medical Affairs, Acadia Pharmaceuticals Inc, San Diego, CA USA
24 6 2024
24 6 2024
9 2024
11 3 441449
16 5 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
Background

Reducing falls and fractures remains an important clinical goal in managing older residents with Parkinson’s disease psychosis (PDP) in long-term care/nursing home (LTC/NH) settings.

Objectives

This analysis examined risk of all-cause falls or fractures among PDP residents on continuous monotherapy with pimavanserin (PIM) versus (i) other atypical antipsychotics (AAPs) [quetiapine (QUE), risperidone (RIS), olanzapine (OLA), aripiprazole (ARI)] and (ii) QUE.

Methods

A retrospective analysis of parts A, B, and D claims from a 100% Medicare sample (2013–2019) in LTC/NH settings was conducted. LTC/NH residents in the USA initiating continuous monotherapy (PIM versus other AAPs; PIM versus QUE) for ≥ 6 months between 01 January 2014 and 31 December 2018 were 1:1 propensity score matched (PSM) on 31 variables (age, sex, race, region, and 27 Elixhauser comorbidities). Outcomes included three measures: risks of falls only, fractures only, and falls/fractures during 6-months follow-up. Demographic characteristics were described using chi-square and t-tests. Generalized linear models were used to assess difference in risks of falls/fractures.

Results

Of 7187 residents, 47.59% (n = 3420) were female and mean age was 78.8 (± 7.75) years. In total, 14% (n = 1005) were on PIM and 86% (n = 6182) were on other AAPs. After PSM, falls only among PIM residents (n = 1005) was 4.58% (n = 46) versus 7.66% (n = 77) for other AAPs (n = 1005) [relative risk (RR) = 0.63 (0.46, 0.86), p < 0.05] and 8.26% (n = 83) for QUE (n = 1005) residents (p < 0.05). Fractures only among PIM residents was 1.39% (n = 14) compared with 2.09% (n = 21) for other AAPs (p = 0.31) and 1.89% (n = 19) for QUE (p = 0.49), respectively. Taken together, falls/fractures among PIM residents were 5.67% (n = 57) versus 9.05% (n = 91) for other AAPs [RR = 0.63 (0.46, 0.86), p < 0.05] and 9.55% (n = 96) for QUE (p < 0.05), respectively.

Conclusions

In this analysis of LTC/NH residents with PDP, PIM had a 37% and 41% lower risk of all-cause falls/fractures versus other AAPs and versus QUE, respectively.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40801-024-00433-2.

http://dx.doi.org/10.13039/100014387 ACADIA Pharmaceuticals issue-copyright-statement© Springer Nature Switzerland AG 2024
==== Body
pmcKey Points

Our research suggests that residents that initiate pimavanserin may have a lower risk for falls or fractures compared with residents treated with other atypical antipsychotics in long-term care or nursing home (LTC/NH) settings.	
The results showed that pimavanserin patients had a 37% decrease in risk of all-cause falls/fractures compared with other atypical antipsychotics and a 41% decrease when compared with quetiapine only.	

Background

Falls and fractures are one of the major causes of morbidity and mortality among older residents in long-term care (LTC) and nursing home (NH) facilities in the USA [1]. The agency for health care research and quality reports that annual rate of falls among the 1.6 million nursing facility residents is at least 50%; with 1 in 3 of those falling repeatedly in a year [2]. It is estimated that approximately 10–25% of those with falls have a serious injury such as fractures [3, 4]. Falls and fractures are known to be drivers that reduce NH residents’ functioning and quality of life, increase NH staff burden, and contribute to a growing NH crisis in the nation [5].

One of the main causes of falls among older residents in LTC/NH facilities is the increasing prevalence of chronic diseases such as Parkinson’s disease (PD) [7, 8]. Some estimates suggest that approximately 5–7% of LTC/NH residents have PD, with the numbers expected to rise in the aging population [6]. Among residents with PD, nonmotor symptoms related to psychosis (i.e., hallucinations and delusions) and cognitive disorders are not only risk factors for premature NH placement and mortality, but they have also been implicated as risk factors for falls and fractures [8]. Emerging research suggests that risk of falls and fractures is known to be higher among residents with PD psychosis (PDP) compared with those without psychosis [7, 8].

Although residents with PD who are not on PD-specific maintenance treatments are more likely to fall, residents who are adequately treated may also be prone to falls due to adverse effects brought on by antipsychotics or other medications that may impair cognition (e.g., narcotics, benzodiazepines, hypnotics or sleeping agents, anticholinergics, muscle relaxants) [9]. AGS Beers criteria and other studies suggest that off-label atypical antipsychotics commonly prescribed to treat neuropsychiatric symptoms such as hallucinations and delusions may also elevate the risk of falls and fractures, potentially due to syncope, sedation, slowed reflexes, loss of balance, and impaired psychomotor function [10, 11]. To date, few studies have examined the risks of falls and fractures among residents treated with different atypical antipsychotics (AAPs) in the LTC/NH setting.

Currently, pimavanserin is the only Food and Drug Administration (FDA) approved AAPs for treating hallucinations and delusions associated with PDP. Previously published research suggested that other AAPs (e.g., quetiapine, risperidone, etc.) continue to be prescribed off-label among residents with PDP, especially in LTC/NH settings [12]. Since reducing falls and fractures remains an important clinical goal in managing older residents in LTC/NH settings, research comparing the risk of falls or fractures among PDP residents treated with different AAPs in such settings is needed. Therefore, a database analysis of Medicare beneficiaries in LTC/NH settings was conducted to examine the risk of falls or fractures among PDP residents treated with pimavanserin (PIM) versus (i) other AAPs [quetiapine (QUE), risperidone (RIS), olanzapine (OLA), aripiprazole (ARI)] and (ii) QUE only.

Methods

Data Source and Study Population

A retrospective analysis of data from the Center for Medicare and Medicaid Services (CMS) 100% Medicare fee-for-service (FFS) claims of PDP residents in long-term care/nursing home (LTC/NH) facilities was conducted. The Medicare program is the primary public health insurer for all US residents aged 65 years and above, as well as selected individuals under 65 years with disabilities and end-stage renal disease. As of 2019, the 100% Medicare sample represented all 63 million US Medicare beneficiaries, encompassing claims for medical services from inpatient (Part A) and outpatient (Part B), and pharmacy services (Part D). It is important to note that Medicare parts A, B, and D cover hospital insurance, medical insurance, and pharmacy insurance, respectively. Medicare FFS is the traditional Medicare program, where healthcare providers are reimbursed based on a fee schedule for each service provided to the beneficiary, determined by the Medicare annual fee schedule.

For this study, eligible sample of residents in LTC/NH setting within the PDP population were identified using a combination of parts A, B, and D claims from 1 January 2013 to 31 December 2019. The PDP population included residents identified from ≥ 1 ICD-9 and ICD-10 diagnostic claim of 332.0 and G20, respectively, for PD with a concurrent psychosis diagnosis (occurrence of ≥ 1 psychosis or psychotic disorder diagnostic claim: F06.0, F06.2, F22, F23, F28, F29, H53.16, R44.0, R44.1, R44.2, R44.3) (see Supplementary Table 1). This analysis was conducted in accordance with the CMS data use agreement that was established after New England Institutional Review Board review and approval.

Study Design and Population

Residents with PDP in the LTC/NH setting who were prescribed and maintained continuously for at least 6 months on PIM monotherapy, other AAPs monotherapy, or QUE-only monotherapy continuously (post-index) between January 2014 and December 2018 formed the final study population. In addition to the comparative cohort of PIM versus “other AAPs” cohort, a “QUE only” cohort was used as a second comparator group as a secondary analysis. This analysis was conducted in compliance with HIPAA under a CMS data use agreement that was established pursuant to a New England Institutional Review Board review and approval. The index date among the eligible sample was identified as the date of first prescription for PIM, other AAPs, or QUE only within LTC/NH settings. Only residents without prior use of any AAPs or PIM for at least 6 months prior to the index date were included (Supplementary Fig. 1). All residents with PDP with a pre-index diagnosis of psychosis, secondary parkinsonism, delirium, other psychotic disorders, alcohol/drug-induced psychosis, schizophrenia, paranoia, or personality disorders were also excluded from the study population. A list of diagnosis codes used for the inclusion/exclusion criteria are given in Supplementary Table 1. Study participant selection process is provided in Fig. 1.Fig. 1. Study Population Selection. PD Parkinson’s disease, PDP Parkinson’s disease psychosis, AAPs atypical antipsychotics, PIM pimavanserin. *Diagnosis of secondary parkinsonism, delirium, other psychotic disorder, alcohol/drug-induced psychosis, schizophrenia, paranoia, or personality disorders. †Residents treated with other AAPs (n = 6,182) i.e., risperidone (n = 668), olanzapine (n = 316), aripiprazole (n = 188), and quetiapine (n = 5010)

Covariates

Pre-index baseline characteristics including age, sex, race or ethnicity, region, clinical comorbidities, and coexisting insomnia or dementia status were examined during 6 months prior to the index date. Clinical comorbidities were evaluated using the Elixhauser comorbidity indexes during the pre-index period.

Outcomes

Falls, Fractures, and Falls/Fractures

Falls were identified from ICD-9 or ICD-10 diagnostic claims for at least any one of the following during the 6-month follow-up: falls on the same level, falls from different level, or unspecified falls for any other reason. Fractures were defined using ICD-9 or ICD-10 diagnostic claims for hip fractures, pelvic, or femur fractures. Additionally, a composite outcome of either falls or fractures were also analyzed. The specific ICD-9 or ICD-10 diagnostic codes used to define these outcomes are explained in detail in Supplementary Table 2.

Propensity Score Matching (PSM)

Residents initiating PIM versus other AAPs or versus QUE only were propensity score matched using a 1:1 ratio in a pairwise fashion to create a balanced sample between the cohorts. Propensity scores were calculated using multivariable logistic regression on resident age, sex, race, region, and 27 of 31 Elixhauser comorbidity characteristics. Four Elixhauser comorbidities such as psychosis, human immunodeficiency virus (HIV), alcohol abuse, and substance abuse were not used in propensity score matching. These 31 variables were chosen as covariates in the propensity score matching as they were hypothesized to be potential confounders based on clinical and statistical plausibility to be associated with the falls/fracture outcomes. Two other concurrent conditions, insomnia and dementia, were used as controlling variables in the regression analysis of outcomes. Residents with psychosis in the pre-index (i.e., baseline) were excluded in this analysis and data for residents with HIV, alcohol abuse, and substance use may be suppressed by CMS to accommodate resident confidentiality and would not have allowed an appropriate method of matching [13–16]. A greedy nearest neighbor matching algorithm was used for matching as well as other matching details are described elsewhere [17]. Covariate balance was assessed using standardized mean differences (SMDs) of < 0.1 between PIM and other AAPs beneficiaries for each of the comorbidities. All missing data were excluded before matching and the final, matched sample had no missing data. The same methodology was repeated for the secondary analysis of PIM versus QUE.

Statistical Analysis

Baseline resident demographics (e.g., sex, age) and clinical characteristics (e.g., Elixhauser comorbidities and other comorbidities such as dementia or insomnia) among residents in matched PIM versus other AAPs (or QUE-only) cohort were described using frequencies and proportions after propensity score matching. Additionally, proportion of residents on specific AAPs such as QUE, RIS, OLA, and ARI in the other AAPs cohort before and after matching were examined. Descriptive statistics were reported as frequencies and percentages for categorical variables, and mean, median, and range for continuous variables. Chi-square tests (categorical measures), t-tests, and Wilcoxon rank sum tests (continuous measures) were used to describe differences in outcomes associated with PIM versus other AAPs.

Risk of falls/fractures among PIM versus other AAPs and PIM versus QUE residents (the secondary analysis) were compared using log binomial regression models, controlling for age, gender, region, race, coexisting insomnia, or coexisting dementia. Relative risk (RR) ratios and 95% confidence intervals are reported for 6-months follow-up. Unless otherwise specified, the statistical significance was set to a threshold of p < 0.05. All analysis were conducted using SAS Enterprise Server via the CMS Virtual Research Data Center.

Results

Of the 7187 residents who initiated continuous monotherapy of AAPs with 6-month follow-up, 14% (n = 1005) were prescribed PIM, 86% (n = 6182) were prescribed other AAPs [QUE, 70% (n = 5010); RIS, 9.29% (n = 668); OLA, 4.40% (n = 316); ARI, 2.62% (n = 188)]. The mean (SD) age for the study cohort was 78.8 (± 7.75) years and 47.59% (n = 3420) were female. The mean age across the two cohorts (PIM, other AAPs) was similar and rates of males and females were comparable. Resident characteristics for PIM versus other AAPs cohort in a matched cohort are described in Table 1, while the clinical comorbidity profile for PIM versus other AAPs cohort after matching is described in Table 2. Prior to matching, rates of Elixhauser comorbidities between PIM and the other AAPs cohorts were significantly different; however, after 1:1 matching, rates between the cohorts were largely balanced. The proportion of patients with insomnia or dementia were significantly higher in the other AAP or QUE cohorts.Table 1 Resident Demographics, PIM versus Other AAPs (Matched to PIM) Cohort

	PIM (n = 1005)	Other AAPs
(n = 1005)	SMD	
Age (in years)				
 Mean (SD)	76.52 (7.53)	77.01 (7.34)	0.066	
 Median (IQR)	77 (71, 82)	77 (72, 82)		
 Minimum, maximum	51, 97	52, 98		
Female, n (%)	495 (49.25%)	496 (49.35%)	0.002	
Race				
 White	909 (90.45)	925 (92.04)	0.056	
 Black	38 (3.78)	40 (3.98)	0.010	
 Other	18 (1.79)	12 (1.19)	0.049	
 Asian	16 (1.59)	NR	0.084	
 Hispanic	NR	NR	0.010	
 Native American	NR	NR	0.017	
 Unknown	NR	NR	0.011	
Region				
 Midwest	233 (23.18)	170 (16.92)	0.157	
 South	397 (39.50)	371 (36.92)	0.053	
 Northeast	217 (21.59)	380 (37.81)	0.361	
 West	158 (15.72)	84 (8.36)	0.228	
AAPs atypical antipsychotics, IQR interquartile range, NR not reported, NS not significant, PIM pimavanserin, SD standard deviation, SMD standardized mean difference

Note: NR, Redacted values due to the CMS cell suppression policy threshold for display of data (values < 11 individuals)

Table 2 Baseline Comorbidities, Matched PIM versus Other AAPs

Comorbidities, n (%)	PIM (n = 1005, %)	Other AAPs (n = 1005, %)	SMD	
Congestive heart failure	134 (13.33%)	141 (14.03%)	0.020	
Cardiac arrhythmia	222 (22.09%)	227 (22.59%)	0.012	
Valvular disease	90 (8.96%)	87 (8.66%)	0.011	
Peripheral vascular

disease

	246 (24.48%)	238 (23.68%)	0.019	
Hypertension uncomplicated	730 (72.64%)	690 (68.66%)	0.087	
Hypertension complicated	143 (14.23%)	125 (12.44%)	0.053	
Paralysis	15 (1.49%)	15 (1.49%)	0.00	
Other neurological

disorders

	961 (95.62%)	974 (96.92%)	0.068	
Chronic pulmonary

disease

	148 (14.73%)	132 (13.13%)	0.046	
Diabetes uncomplicated	205 (20.40%)	199 (19.80%)	0.015	
Diabetes complicated	129 (12.84%)	106 (10.55%)	0.071	
Hypothyroidism	218 (21.69%)	202 (20.10%)	0.039	
Renal failure	125 (12.44%)	123 (12.24%)	0.006	
Liver disease	15 (1.49%)	14 (1.39%)	0.008	
Solid tumors w/o metastasis	85 (8.46%)	89 (8.86%)	0.014	
Peptic ulcer	NR	11 (1.09%)	0.042	
Lymphoma	11 (1.09%)	NR	0.010	
Pulmonary circulation disorders	37 (3.68%)	33 (3.28%)	0.022	
Coagulopathy	41 (4.08%)	43 (4.28%)	0.010	
Metastatic cancer	NR	13 (1.29%)	0.112	
Rheumatoid

arthritis

	39 (3.88%)	29 (2.89%)	0.055	
Obesity	68 (6.77%)	64 (6.37%)	0.016	
Weight loss	84 (8.36%)	83 (8.26%)	0.004	
Fluid and

Electrolyte

Disorders

	241 (23.98%)	274 (27.26%)	0.075	
Blood loss anemia	12 (1.19%)	14 (1.39%)	0.018	
Deficiency anemia	95 (9.45%)	100 (9.95%)	0.017	
Depression	481 (47.86%)	473 (47.06%)	0.016	
Additional comorbid conditions, n (%)	
  Insomnia	290 (28.85%)	358 (35.61%)	*	
  Dementia	727 (72.3%)	851 (84.7%)	*	
AAPs atypical antipsychotics, PIM pimavanserin, SMD standardized mean difference

*SMD for insomnia and dementia were not calculated as they are not part of Elixhauser comorbidities, instead p-values were reported (p < 0.05)

Note: NR, Redacted values due to the CMS cell suppression policy threshold for display of data (values < 11 individuals)

Figure 2 shows the risk of falls or fractures for PIM versus other AAPs. Among the matched cohort, the risk for fractures only were 1.39% (n = 14) for PIM compared with 2.09% (n = 21) for other AAPs. PIM residents also experienced lower risk of falls only [4.58% (n = 46)] compared with other AAPs residents [7.66% (n = 77)] [RR = 0.60 (0.42, 0.85), p < 0.05]. Risk for falls or fractures among PIM residents was 5.67% (n = 57) versus 9.05% (n = 91) for other AAPs [RR = 0.63 (0.46, 0.86), p < 0.05] (see Fig. 2 and Table 3).Fig. 2 Risk of Falls/Fractures: PIM versus Other AAPs. AAPs atypical antipsychotics, NS not significant, PIM pimavanserin

Table 3 Risks of falls only, fractures only, and falls or fractures among PIM versus other AAP-treated residents at 6-months follow-up

Outcome events	PIM (n = 1005)	Other AAPs (n = 1005)	RR (95% CI)	p-value	PIM (n = 1005)	QUE (n = 1005)	RR
(95% CI)	p-value	
Fractures only	
 n (%)	14 (1.4)	21 (2.1)	0.67 (0.34, 1.30)	NS	14 (1.4)	19 (1.9)	0.74 (0.37, 1.46)	NS	
Falls only	
 n (%)	46 (4.6)	77 (7.7)	0.60 (0.42, 0.85)	< 0.05	46 (4.6)	83 (8.3)	0.55 (0.39, 0.79)	< 0.05	
Falls or fractures	
 n (%)	57 (5.7)	91 (9.1)	0.63 (0.46, 0.86)	< 0 .05	57 (5.7)	96 (9.6)	0.59 (0.43, 0.81)	< 0.05	
AAPs atypical antipsychotics, NS not significant, PIM pimavanserin, QUE quetiapine, RR relative risk

A secondary analysis of the matched PIM and QUE cohorts (Fig. 3) showed a nonsignificant difference in fracture risk between the cohorts. PIM residents had a 1.39% fracture risk, while those who received QUE had a 1.89% risk (p-value: ns). Risk for falls only were significantly lower for PIM residents (4.6%) compared with 8.26% for QUE [RR = 0.55 (0.39, 0.79), p < 0.05]. The proportion of residents with falls or fractures was lower in the PIM group (5.67% versus 9.55%) compared with the QUE group [RR = 0.59 (0.43, 0.81), p < 0.05] (see Fig. 3 and Table 3).Fig. 3 Risk of Falls/Fractures: PIM versus QUE. NS not significant, PIM pimavanserin, QUE quetiapine

Discussion

While published research before the advent of pimavanserin implicated AAPs medication use with an increased risk of falls and fractures among older nursing home residents, not many studies have examined the association of pimavanserin and other AAPs use for falls or fractures among residents with PDP in nursing home residents [18, 19]. The current analysis adds to the body of published literature comparing the risk of fall/fracture outcomes among PDP residents treated with PIM versus other AAPs and PIM versus QUE in an LTC/NH setting.

Previous research had also suggested that all AAPs may have higher, yet similar, rates of falls or fractures compared with nonusers [20]. Recently published claims data analysis of a population with PDP that have either commercial insurance or Medicare advantage coverage suggests that pimavanserin demonstrated no increase in the risk of falls or fractures compared with other AAPs [21]. While nursing home residents may have been included in the study, they were not separately discussed or analyzed. Our research suggests that residents that initiate PIM may have a lower risk for falls or fractures compared with residents treated with other AAPs in LTC/NH setting. A few plausible reasons may explain why PIM may have lower risks of falls or fall related injuries such as fractures. First, it is widely acknowledged that other AAPs such as olanzapine, risperidone, and quetiapine cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. On the other hand, patients treated with pimavanserin in placebo-controlled studies had low rates of orthostatic hypotension or sedation-related adverse events [22]. While these are not causal in nature, low rates of orthostatic hypotension or sedation may be associated with lower rates of falls/fractures observed with PIM. Second, it should be noted that in a phase 3, 6-week, double-blind randomized controlled trial (RCT), PIM significantly reduced the frequency and/or severity of hallucination and/or delusions associated with Parkinson’s disease psychosis versus placebo, without impairing motor function [23]. These effects may be especially critical in the context of treating residents with PDP given their motor impairment associated with PD symptoms without the potential for increasing falls and associated fractures.

While we examined a balanced sample of residents to the extent possible, it cannot be ruled out that residents with potential concomitant use of antidepressants, benzodiazepines, acetylcholinesterase inhibitors, memantine, selected antihypertensives, and other drugs with potentially higher risk of falls may also have played a role in the differential risk of falls or fractures that was observed in this analysis. It should be noted that in this analysis, the study did not control for prior falls/fractures since controlling for the same baseline variables in the causal pathway can hide true differences in follow-up outcomes and bias the results. Since this analysis assessed 6-month risk of falls and/or fractures among continuously enrolled patients with least 6-month continuous index monotherapy, patients who discontinue monotherapy, switched, or added any AAPs during the 6-month post-index period were excluded from analysis. Thus, the study had none that switched from one AAP medication to another or added another atypical antipsychotic during the follow-up period.

In the US, falls and fall-related injuries such as fractures constitute approximately 6% of total Medicare spending annually [24]. Falls and fractures have been known to contribute to greater functional impairment and increased physical and mental disabilities. Additionally, they may result in premature deaths; in 2017, over 28,000 fall-related deaths were identified among the elderly in USA [25]. From 2004 to 2017, the rate of fatal fall injuries increased 35% [26]. The risk of mortality within 1 year after experiencing a hip fracture is estimated to be around 40% among residents of nursing homes [27]. Several studies including systematic literature reviews have reported the increased risk of falls and fall-related fractures among nursing home residents treated with psychotropic medications such as AAPs in the last few decades [7–11]. However, few studies have reported the fall risk differences between specific antipsychotics to help clinicians in making evidence-based prescribing decisions for NH residents. It is widely acknowledged that inappropriate use of AAPs among NH residents may be one of the culprits in higher rates of falls, fractures, cerebrovascular events such as stroke, and ultimately death [10, 11]. The falls prevention program instituted by CMS has implemented strategies to limit the use of AAPs through onerous documentation measures and gradual dose reduction aimed toward dose tapering, among others [28]. Our study primarily focused on falls and fractures to hip, femur, and pelvic regions as these were the most detrimental (fall-related) fractures in the elderly. Hip fractures in the elderly not only affects mobility but also result in high mortality [29]. Therefore, arms, wrist, fingers, or other bone-related fractures that may result from falls are not reported in this analysis. Previous research that utilized claims-based algorithm for identifying the incidence of fractures were based on claims data integrated with electronic medical records; our analysis relied on ICD-9/10 diagnostic codes for identification of falls or fractures since our data source included only claims. Notwithstanding the potential for underestimating falls in diagnostic claims, this analysis provides a valid measure of assessing the incidence of falls [30]. While much research is needed, we believe this is the first analysis to develop an evidence base to examine the fall-risk level differences among residents treated with specific AAPs such as PIM or QUE. These results may provide important insights regarding the clinical value of specific AAPs as it pertains to fall risk and help prescribers in evidence-based prescription decision-making. Future investigations examining the association between characteristics and risk of falls/fractures may be needed.

Limitations

As with any claims analysis, this research has a few limitations. First, sampling errors due to miscoding or under-coding of claims may have occurred in this analysis of claims data that are primarily used for billing and reimbursement purposes. To the extent the coding errors can be minimized, the use of a second confirmatory diagnostic claim to identify resident sample may have reduced potential sampling errors due to coding issues. Second, the study may have resulted in biased estimates due to the absence of variables such as medical/clinical characteristics, socio economic characteristics or other factors in claims data. Third, the PIM cohort had lower obesity, higher diabetes, and higher hypertension rates (Table 2) even after PSM, suggesting residual imbalance may exist. Fourth, baseline or prior risk of falls and fractures were not included as a covariate in the adjusted analysis. Fifth, while differential usage of various antihypertensives at differing dose ranges may play a contributing role in falls and fractures, granular details about the intensity of these agents were outside of scope of this research. Finally, our analysis could not control for underlying PD or PDP severity since severity cannot be defined in claims data. Our study primarily focused on fall and fractures to hip, femur, and pelvic regions as these were the most common fall-related fractures in the elderly. Since only major fractures were considered, this analysis might not capture the full picture of other fractures resulting from falls. Fractures of the wrist, fingers, or other bones that may result from falls could be underestimated. While our study examined the 6-month risk differences among matched cohort of LTC/NH residents receiving either PIM or other AAPs (or QUE) for PDP, residual confounding due to unobserved variables (e.g., medications, eyesight related problems, environmental hazards, etc.) that can increase the risk of falls or fractures cannot be ruled out. While this analysis included propensity score-matched cohorts, it is plausible that residual confounding may exist due to variables not included in the analysis. Notwithstanding this limitation, these results add to the body of literature in describing the potential lower risk of falls or fractures with PIM treatment versus other AAP and provide guidance about the choice of appropriate AAPs to treat PDPs to clinical and formulary decisionmakers.

It should be noted that the other AAPs including QUE are known to increase the risk of falls and consequently fall-related fractures due to several reasons including increased sedation, exacerbation of mild cognitive problems, and extrapyramidal symptoms, among others [31]. While this study did not examine the predictors of falls or fractures in this vulnerable population, future investigations examining the predictors of falls in PDP patients are warranted.

Conclusions

In this analysis of residents with PDP that have an LTC/NH stay from the 100% Medicare sample, PIM monotherapy resulted in nearly a 40% lower risk of falls only and falls/fractures compared with other AAPs or QUE. Risks of fractures only were no different between PIM versus other AAP or QUE residents. Overall, the lower risk of falls/fractures observed among PIM monotherapy residents in this analysis may be suggestive of a more favorable clinical benefit risk profile with PIM compared with other AAPs including QUE in LTC/NH facilities. Future studies examining other predictive risk factors for falls or fractures among LTC/NH residents receiving PIM versus other AAPs may provide additional insights and guidance to clinicians.

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 47 KB)

Abbreviations

AAP Atypical antipsychotic

CMS Centers for Medicare and Medicaid Services

PD Parkinson’s disease

PDP Parkinson’s disease psychosis

LTC Long-term care

NH Nursing homes

PIM Pimavanserin

QUE Quetiapine

RIS Risperidone

OLA Olanzapine

ARI Aripiprazole

Safiuddin Shoeb Syed, employee of Anlitiks, contributed to writing, formatting, and preparation of the manuscript for submission to the journal.

Declarations

Author Contributions

KR, NR, and DD were responsible for study conception and design; author KR were responsible for acquisition of data; authors KR, NR, DG, and DD were responsible for data analysis and drafting and revisions of the manuscript. All authors read and approved the final version of the manuscript.

Conflicts of Interest

The authors report no conflict of interest in this work.

Ethics Approval:

This analysis was conducted in compliance with HIPAA under a CMS data use agreement that was established pursuant to a New England Institutional Review Board review and Approval.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Availability of Data and Material

The CMS 100% sample is not publicly available and has strict restrictions on how they may be accessed, analyzed, and reported even as aggregate data. As such, these data sets, data reports, and all other materials are not allowable by CMS, except as aggregate tables that we have provided in the manuscript.

Code Availability

The software or custom code is not applicable.

Declaration of Funding

This study was financially sponsored by Acadia Pharmaceuticals. The funding supports conducting research and manuscript preparation.
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References

1. Vaishya R Vaish A Falls in older adults are serious Indian J Orthop. 2020 54 1 69 74 10.1007/s43465-019-00037-x 32257019
Vaishya R, Vaish A. Falls in older adults are serious. Indian J Orthop. 2020;54(1):69–74. 10.1007/s43465-019-00037-x.32257019 10.1007/s43465-019-00037-x
2. Falls. Patient Safety Network. https://psnet.ahrq.gov/primer/falls. Published September 7, 2019. Accessed 3 Apr 2023.
3. Guideline for the prevention of falls in older persons American Geriatrics Society, British Geriatrics Society, and American Academy of Orthopaedic Surgeons Panel on Falls Prevention J Am Geriatr Soc 2001 49 5 664 672 11380764
Guideline for the prevention of falls in older persons. American Geriatrics Society, British Geriatrics Society, and American Academy of Orthopaedic Surgeons Panel on Falls Prevention. J Am Geriatr Soc. 2001;49(5):664–72.11380764
4. Bogardus ST Jr. Another Fall. Patient Safety Network. AHRQ. April 1, 2003. https://psnet.ahrq.gov/web-mm/another-fall. Accessed 1 Feb 2023.
5. Falls. Agency for Healthcare Research and Quality (AHRQ). Accessed February 1, 2023. Falls | Agency for Healthcare Research and Quality (ahrq.gov)
6. Mitchell SL Kiely DK Kiel DP Lipsitz LA The epidemiology, clinical characteristics, and natural history of older nursing home residents with a diagnosis of Parkinson's disease J Am Geriatr Soc 1996 44 4 394 399 10.1111/j.1532-5415.1996.tb06408.x 8636583
Mitchell SL, Kiely DK, Kiel DP, Lipsitz LA. The epidemiology, clinical characteristics, and natural history of older nursing home residents with a diagnosis of Parkinson’s disease. J Am Geriatr Soc. 1996;44(4):394–9. 10.1111/j.1532-5415.1996.tb06408.x.8636583 10.1111/j.1532-5415.1996.tb06408.x
7. Wetmore JB Li S Yan H Increases in institutionalization, healthcare resource utilization, and mortality risk associated with Parkinson disease psychosis: Retrospective cohort study Parkinsonism Relat Disord 2019 68 95 101 10.1016/j.parkreldis.2019.10.018 31679990
Wetmore JB, Li S, Yan H, et al. Increases in institutionalization, healthcare resource utilization, and mortality risk associated with Parkinson disease psychosis: Retrospective cohort study. Parkinsonism Relat Disord. 2019;68:95–101. 10.1016/j.parkreldis.2019.10.018.31679990 10.1016/j.parkreldis.2019.10.018
8. Forns J, Layton JB, Bartsch J, et al. Increased risk of falls and fractures in patients with psychosis and Parkinson disease. PLoS One. 2021;16(1):e0246121. Published 2021 Jan 27. 10.1371/journal.pone.0246121
9. Stroup TS Gray N Management of common adverse effects of antipsychotic medications World Psychiatry 2018 17 3 341 356 10.1002/wps.20567 30192094
Stroup TS, Gray N. Management of common adverse effects of antipsychotic medications. World Psychiatry. 2018;17(3):341–56. 10.1002/wps.20567.30192094 10.1002/wps.20567
10. Steinberg M Lyketsos CG Atypical antipsychotic use in patients with dementia: managing safety concerns Am J Psychiatry 2012 169 9 900 906 10.1176/appi.ajp.2012.12030342 22952071
Steinberg M, Lyketsos CG. Atypical antipsychotic use in patients with dementia: managing safety concerns. Am J Psychiatry. 2012;169(9):900–6. 10.1176/appi.ajp.2012.12030342.22952071 10.1176/appi.ajp.2012.12030342
11. Wei YJ Simoni-Wastila L Lucas JA Brandt N Fall and fracture risk in nursing home residents with moderate-to-severe behavioral symptoms of Alzheimer's disease and related dementias initiating antidepressants or antipsychotics J Gerontol A Biol Sci Med Sci 2017 72 5 695 702 10.1093/gerona/glw095 27247274
Wei YJ, Simoni-Wastila L, Lucas JA, Brandt N. Fall and fracture risk in nursing home residents with moderate-to-severe behavioral symptoms of Alzheimer’s disease and related dementias initiating antidepressants or antipsychotics. J Gerontol A Biol Sci Med Sci. 2017;72(5):695–702. 10.1093/gerona/glw095.27247274 10.1093/gerona/glw095
12. Chen JJ Hua H Massihi L Portillo I Alipour A Ondo W Dashtipour K Systematic literature review of quetiapine for the treatment of psychosis in patients with Parkinsonism J Neuropsychiatry Clin Neurosci 2019 31 3 188 195 10.1176/appi.neuropsych.18080180 30848989
Chen JJ, Hua H, Massihi L, Portillo I, Alipour A, Ondo W, Dashtipour K. Systematic literature review of quetiapine for the treatment of psychosis in patients with Parkinsonism. J Neuropsychiatry Clin Neurosci. 2019;31(3):188–95. 10.1176/appi.neuropsych.18080180.30848989 10.1176/appi.neuropsych.18080180
13. Sewell DD Jeste DV Atkinson JH HIV-associated psychosis: a study of 20 cases. San Diego HIV Neurobehavioral Research Center Group Am J Psychiatry 1994 151 2 237 242 10.1176/ajp.151.2.237 8296896
Sewell DD, Jeste DV, Atkinson JH, et al. HIV-associated psychosis: a study of 20 cases. San Diego HIV Neurobehavioral Research Center Group. Am J Psychiatry. 1994;151(2):237–42. 10.1176/ajp.151.2.237.8296896 10.1176/ajp.151.2.237
14. Collins RL, Beckett MK, Burnam MA. Mental health and substance abuse issues among people with HIV Lessons from HCSUS. 2007.
15. Substance Abuse and Mental Health Services Administration. Co-occurring disorders and other health conditions. https://www.samhsa.gov/medication-assisted-treatment/medications-counseling-related-conditions/co-occurring-disorders. Published 2022, April 21. Updated 21 April, 2022. Accessed 29 July 2022.
16. Sterling S Chi F Hinman A Integrating care for people with co-occurring alcohol and other drug, medical, and mental health conditions Alcohol Res Health 2011 33 4 338 349 23580018
Sterling S, Chi F, Hinman A. Integrating care for people with co-occurring alcohol and other drug, medical, and mental health conditions. Alcohol Res Health. 2011;33(4):338–49.23580018
17. Rajagopalan K Rashid N Kumar S Doshi D Health care resource utilization patterns among patients with Parkinson's disease psychosis: analysis of Medicare beneficiaries treated with pimavanserin or other-atypical antipsychotics J Med Econ 2023 26 1 34 42 10.1080/13696998.2022.2152600 36444507
Rajagopalan K, Rashid N, Kumar S, Doshi D. Health care resource utilization patterns among patients with Parkinson’s disease psychosis: analysis of Medicare beneficiaries treated with pimavanserin or other-atypical antipsychotics. J Med Econ. 2023;26(1):34–42. 10.1080/13696998.2022.2152600.36444507 10.1080/13696998.2022.2152600
18. Rissardo JP Durante Í Sharon I Fornari Caprara AL Pimavanserin and Parkinson's disease psychosis: a Narrative review Brain Sci 2022 12 10 1286 10.3390/brainsci12101286 36291220
Rissardo JP, Durante Í, Sharon I, Fornari Caprara AL. Pimavanserin and Parkinson’s disease psychosis: a Narrative review. Brain Sci. 2022;12(10):1286. 10.3390/brainsci12101286.36291220 10.3390/brainsci12101286
19. Jethwa KD Onalaja OA Antipsychotics for the management of psychosis in Parkinson's disease: systematic review and meta-analysis BJPsych Open. 2015 1 1 27 33 10.1192/bjpo.bp.115.000927 27703720
Jethwa KD, Onalaja OA. Antipsychotics for the management of psychosis in Parkinson’s disease: systematic review and meta-analysis. BJPsych Open. 2015;1(1):27–33. 10.1192/bjpo.bp.115.000927.27703720 10.1192/bjpo.bp.115.000927
20. Liperoti R Onder G Lapane KL Conventional or atypical antipsychotics and the risk of femur fracture among elderly patients: Results of a case-control study J Clin Psychiatry 2007 68 6 929 934 10.4088/jcp.v68n0616 17592919
Liperoti R, Onder G, Lapane KL, et al. Conventional or atypical antipsychotics and the risk of femur fracture among elderly patients: Results of a case-control study. J Clin Psychiatry. 2007;68(6):929–34. 10.4088/jcp.v68n0616.17592919 10.4088/jcp.v68n0616
21. Layton JB Forns J Turner ME Falls and fractures in patients with Parkinson's disease-related psychosis treated with pimavanserin vs atypical antipsychotics: a cohort study Drugs Real World Outcomes. 2022 9 1 9 22 10.1007/s40801-021-00284-1 34718963
Layton JB, Forns J, Turner ME, et al. Falls and fractures in patients with Parkinson’s disease-related psychosis treated with pimavanserin vs atypical antipsychotics: a cohort study. Drugs Real World Outcomes. 2022;9(1):9–22. 10.1007/s40801-021-00284-1.34718963 10.1007/s40801-021-00284-1
22. Ballard CG Kreitzman DL Isaacson S Long-term evaluation of open-label pimavanserin safety and tolerability in Parkinson's disease psychosis Parkinsonism Relat Disord 2020 77 100 106 10.1016/j.parkreldis.2020.06.026 32712560
Ballard CG, Kreitzman DL, Isaacson S, et al. Long-term evaluation of open-label pimavanserin safety and tolerability in Parkinson’s disease psychosis. Parkinsonism Relat Disord. 2020;77:100–6. 10.1016/j.parkreldis.2020.06.026.32712560 10.1016/j.parkreldis.2020.06.026
23. Cummings J Ballard C Tariot P Pimavanserin: potential treatment for dementia-related psychosis J Prev Alzheimers Dis. 2018 5 4 253 258 10.14283/jpad.2018.29 30298184
Cummings J, Ballard C, Tariot P, et al. Pimavanserin: potential treatment for dementia-related psychosis. J Prev Alzheimers Dis. 2018;5(4):253–8. 10.14283/jpad.2018.29.30298184 10.14283/jpad.2018.29
24. Florence CS Bergen G Atherly A Burns E Stevens J Drake C Medical costs of fatal and nonfatal falls in older adults J Am Geriatr Soc 2018 66 4 693 698 10.1111/jgs.15304 29512120
Florence CS, Bergen G, Atherly A, Burns E, Stevens J, Drake C. Medical costs of fatal and nonfatal falls in older adults. J Am Geriatr Soc. 2018;66(4):693–8. 10.1111/jgs.15304.29512120 10.1111/jgs.15304
25. Older Adults Fall Prevention. Centers for Disease Control and Prevention. Last updated: September 6, 2023. https://www.cdc.gov/falls/data/index.html. Accessed 17 Nov 2023.
26. Drew JAR Xu D Trends in fatal and nonfatal injuries among older Americans, 2004–2017 Am J Prev Med 2020 59 1 3 11 10.1016/j.amepre.2020.01.008 32201184
Drew JAR, Xu D. Trends in fatal and nonfatal injuries among older Americans, 2004–2017. Am J Prev Med. 2020;59(1):3–11. 10.1016/j.amepre.2020.01.008.32201184 10.1016/j.amepre.2020.01.008
27. Mintz J Duprey MS Zullo AR Identification of fall-related injuries in nursing home residents using administrative claims data [published correction appears in J Gerontol A Biol Sci Med Sci. 2022 May 09;:] J Gerontol A Biol Sci Med Sci 2022 77 7 1421 1429 10.1093/gerona/glab274 34558615
Mintz J, Duprey MS, Zullo AR, et al. Identification of fall-related injuries in nursing home residents using administrative claims data [published correction appears in J Gerontol A Biol Sci Med Sci. 2022 May 09;:]. J Gerontol A Biol Sci Med Sci. 2022;77(7):1421–9. 10.1093/gerona/glab274.34558615 10.1093/gerona/glab274
28. The Falls Management Program: A quality improvement program for nursing facilities. Page last reviewed March 2023. https://www.ahrq.gov/patient-safety/settings/long-term-care/resource/injuries/fallspx.html. Accessed 17 Nov 2023.
29. Alexiou KI Roushias A Varitimidis SE Malizos KN Quality of life and psychological consequences in elderly patients after a hip fracture: a review Clin Interv Aging 2018 13 143 150 10.2147/CIA.S150067 29416322
Alexiou KI, Roushias A, Varitimidis SE, Malizos KN. Quality of life and psychological consequences in elderly patients after a hip fracture: a review. Clin Interv Aging. 2018;13:143–50. 10.2147/CIA.S150067.29416322 10.2147/CIA.S150067
30. Wright NC Daigle SG Melton ME Delzell ES Balasubramanian A Curtis JR The design and validation of a new algorithm to identify incident fractures in administrative claims data J Bone Miner Res 2019 34 10 1798 1807 10.1002/jbmr.3807 31170317
Wright NC, Daigle SG, Melton ME, Delzell ES, Balasubramanian A, Curtis JR. The design and validation of a new algorithm to identify incident fractures in administrative claims data. J Bone Miner Res. 2019;34(10):1798–807. 10.1002/jbmr.3807.31170317 10.1002/jbmr.3807
31. El-Saifi N Moyle W Jones C Tuffaha H Quetiapine safety in older adults: A systematic literature review J Clin Pharm Ther 2016 41 1 7 18 10.1111/jcpt.12357 26813985
El-Saifi N, Moyle W, Jones C, Tuffaha H. Quetiapine safety in older adults: A systematic literature review. J Clin Pharm Ther. 2016;41(1):7–18. 10.1111/jcpt.12357.26813985 10.1111/jcpt.12357
